The development of cardiac hypertrophy in response to a sustained stress is a fundamental property of the heart. This increase in myocardial mass provides a basic compensatory mechanism which allows the heart to meet the demands of an increased workload. Although initially beneficial in terms of maintaining total pump performance, the development of cardiac hypertrophy may ultimately be associated with a depression of the intrinsic contractile state of each individual unit of myocardium, which, if progressive, may eventuate in circulatory decompensation and the clinical syndrome of heart failure. It is the purpose of this program project to address two principal questions: 1) Is depression of contractile function an invariable consequence of cardiac hypertrophy regardless of the initiating stimulus? and 2) What is the extent to which hypertrophy and any associated depression of cardiac contractility is reversed if the imposed stress is removed? The objective of the proposed program project is to carry out a systematic characterization of the physiologic and biochemical events accompanying cardiac hypertrophy and to examine the effects of removal of the hypertrophy-inciting stimulus. A number of models of pressure and volume overload will be used and the findings correlated with those obtained in patients. The objective of the proposed clinical studies, which will be carried out both in adults and children, is to determine the extent to which myocardial hypertrophy in man is a reversible process. There will be close coordination between the experimental and clinical studies so that the results obtained in the laboratory can be applied readily to the clinical setting, whenever appropriate. An important goal of the characterization of hypertrophy and the determinants of its reversibility is the identification of the factors which should be used in the timing of the decision to operate and which will influence the successful outcome of the procedure.